Patent application title: DRUG DELIVERY COMPOSITION

Abstract:

A drug delivery composition that comprises extruded spheroids. The
spheroids comprise at least one active pharmaceutical ingredient; at
least one extrusion-spheronization aid; at least one superdisintegrant;
and at least one glidant, at least one lubricant, and/or at least one
oil. The spheroids may also be coated. In a further aspect, a drug
delivery composition that comprises coated spheroids that have inert
spheroids and at least one coating for the spheroids. The coating
comprises at least one active pharmaceutical ingredient and at least one
superdisintegrant.

Claims:

1. A drug delivery composition comprising extruded spheroids, the
spheroids comprising:at least one active pharmaceutical ingredient; at
least one extrusion-spheronization aid; at least one superdisintegrant;
and at least one glidant, at least one lubricant, and/or at least one
oil.

2. The drug delivery composition of claim 1, wherein said at least one
active pharmaceutical ingredient is from about 0.1 wt % to about 80 wt %.

3. The drug delivery composition of claim 1, wherein said at least one
active pharmaceutical ingredient is from about 5 wt % to about 70 wt %;
about 10 wt % to about 70 wt %; about 20 wt % to about 60 wt %; about 30
wt % to about 60 wt %; or from about 40 wt % to about 60 wt %.

4. The drug delivery composition of claim 1, wherein said at least one
extrusion-spheronization aid is from about 10 wt % to about 70 wt %; from
about 20 wt % to about 70 wt %; about 30 wt % to about 70 wt %; about 40
wt % to about 70 wt %; about 50 wt % to about 70 wt %; or from about 55
wt % to about 70 wt %.

5. The drug delivery composition of claim 1, wherein said at least one
superdisintegrant is from about 2 wt % to about 70 wt %; from about 20 wt
% to about 70 wt %; about 30 wt % to about 70 wt %; about 40 wt % to
about 70 wt %; about 50 wt % to about 70 wt %; or from about 55 wt % to
about 70 wt %.

6. The drug delivery composition of claim 1, wherein said at least one
glidant is from about 1 wt % to about 20 wt %; from about 1 wt % to about
15 wt %; from about 2 wt % to about 15 wt %; from about 5 wt % to about
15 wt %; or from about 5 wt % to about 10 wt %.

7. The drug delivery composition of claim 1, wherein said at least one
lubricant is from about 0.5 wt % to about 5 wt %; from about 0.5 wt % to
about 4 wt %; from about 0.5 wt % to about 3 wt %; from about 0.5 wt % to
about 2 wt %; or from about 1 wt % to about 2 wt %.

8. The drug delivery composition of claim 1, wherein said at least one oil
is from about 0.5 wt % to about 5 wt %; from about 0.5 wt % to about 4 wt
%; from about 0.5 wt % to about 3 wt %; from about 0.5 wt % to about 2 wt
%; or from about 1 wt % to about 2 wt %.

9. The drug delivery composition of claim 1, further comprising at least
one carbomer, at least one buffering agent, at least one electrolyte,
zein, and/or water.

10. The drug delivery composition of claim 1, wherein said at least one
extrusion-spheronization aid is from about 10 wt % to about 90 wt %, said
at least one superdisintegrant is from about 0.1 wt % to about 70 wt %,
said at least one glidant is from about 0.1 wt % to about 70 wt %, said
at least one lubricant is from about 0.1 wt % to about 70 wt % and said
at least one oil is from about 0.1 wt % to about 50 wt %.

11. The drug delivery composition of claim 1, further comprises at least
one coating.

12. The drug delivery composition of claim 11, wherein said at least one
coating comprises at least one layer of a polymeric film coat; at least
one layer of an enteric coat; at least one layer of a non-enteric coat;
and/or at least one layer of a semi-permeable membrane coat.

13. The drug delivery composition of claim 12, wherein said at least one
layer of an enteric coating comprises at least one enteric material and
at least one superdisintegrant; said at least one layer of a non-enteric
coat comprises at least one non-enteric material and at least one
superdisintegrant; and/or said at least one layer of a semi-permeable
membrane coat comprises at least one semi-permeable membrane material and
at least one superdisintegrant.

14. The drug delivery composition of claim 13, wherein said at least one
superdisintegrant is from about 0.5 wt % to about 55 wt %; from about 0.5
wt % to about 40 wt %; from about 0.5 wt % to about 30 wt %; from about 1
wt % to about 20 wt %; or from about 10 wt % to about 20 wt %.

15. The drug delivery composition of claim 12, wherein each layer further
comprises at least one wicking agent, carragenaan, and at least one
plasticizer.

16. The drug delivery composition of claim 15, wherein said at least one
wicking agent is from about 0.5 wt % to about 55 wt %; from about 0.5 wt
% to about 50 wt %; from about 0.5 wt % to about 40 wt %; from about 5 wt
% to about 40 wt %; or from about 20 wt % to about 40 wt %.

17. The drug delivery composition of claim 15, wherein carragenaan is from
about 0.5 wt % to about 55 wt %; from about 0.5 wt % to about 50 wt %;
from about 0.5 wt % to about 40 wt %; from about 5 wt % to about 40 wt %;
or from about 20 wt % to about 40 wt %.

18. The drug delivery composition of claim 15, wherein the plasticizer is
from about 0.5 wt % to about 25 wt %; from about 1 wt % to about 20 wt %;
from about 5 wt % to about 20 wt %; from about 5 wt % to about 15 wt %;
or from about 1 wt % to about 5 wt %.

19. The drug delivery composition of claim 11, wherein said at least one
coating from about 0.5 wt % to about 50 wt % based on the total weight of
the spheroid and coating.

20. The drug delivery composition of claim 19, wherein said at least one
coating is from about I wt % to about 20 wt %, from about I wt % to about
10 wt %, from about 1 wt % to about 7 wt %, from about 3.5 wt % to about
7 wt %, from about 3.5 wt % to about 6 wt %, or from about 4 wt % to
about 5 wt %.

21. The drug delivery composition of claim 19, wherein the coating is
applied to the spheroids to yield a surface area of about 0.1 mg/cm2
to about 20 mg/cm.sup.2.

22. The drug delivery composition of claim 1, wherein the drug delivery
composition is encapsulated or compressed into a tablet and/or caplet.

23. The drug delivery composition of claim 1, wherein the spheroids are in
a capsule and/or sachet.

24. The drug delivery composition of claim 1, wherein there are different
populations of the spheroids.

25. The drug delivery composition of claim 1, wherein said at least one
active pharmaceutical ingredient comprises chemical or biological
molecules providing a therapeutic, diagnostic, or prophylactic effect in
vivo.

31. A drug delivery composition comprising coated spheroids having inert
spheroids and at least one coating for the spheroids, the coating
comprising at least one active pharmaceutical ingredient and at least one
superdisintegrant.

32. The drug delivery composition of claim 31, wherein said at least one
active pharmaceutical ingredient is from about 0.1 wt % to about 90 wt %.

33. The drug delivery composition of claim 31, whereinsaid at least
onesuperdisintegrant is from about 0.1 wt % to about 80 wt %.

34. The drug delivery composition of claim 31, wherein said at least one
active pharmaceutical ingredient is from about 0.1 wt % to about 80 wt %;
from about 10 wt % to about 80 wt %; from about 20 wt % to about 80 wt %;
from about 30 wt % to about 70 wt %; or from about 40 wt % to about 70 wt
%.

35. The drug delivery composition of claim 31, wherein said at least one
superdisintegrant is from about 0.5 wt % to about 55 wt %; from about 0.5
wt % to about 40 wt %; from about 0.5 wt % to about 30 wt %; from about 1
wt % to about 20 wt %; or from about 10 wt % to about 20 wt %.

36. The drug delivery composition of claim 31, wherein the coating further
comprises at least one of a wicking agent, carageenan and/or a
plasticizer.

37. The drug delivery composition of claim 36, the wicking agent is from
about 0.5 wt % to about 90 wt %; from about 0.5 wt % to about 80 wt %;
from about 0.5 wt % to about 70 wt %; from about 5 wt % to about 60 wt %;
or from about 20 wt % to about 60 wt %.

38. The drug delivery composition of claim 36, the carragenaan is from
about 0.5 wt % to about 90 wt %; from about 0.5 wt % to about 80 wt %;
from about 0.5 wt % to about 70 wt %; from about 5 wt % to about 60 wt %;
or from about 20 wt % to about 60 wt %.

39. The drug delivery composition of claim 36, wherein the plasticizer is
from about 0.5 wt % to about 25 wt %; from about 1 wt % to about 20 wt %;
from about 5 wt % to about 20 wt %; from about 5 wt % to about 15 wt %;
or from about 1 wt % to about 5 wt %.

40. The drug delivery composition of claim 31, wherein said at least one
coating comprises from about 0.1 wt % to about 80 wt % of said at least
one active pharmaceutical ingredient, from about 0.1 wt % to about 50 wt
% of said at least one superdisintegrant, from about 0.5 wt % to about 90
wt % of a wicking agent, and from about 0.5 wt % to about 90 wt % of
carrageenan.

41. The drug delivery composition of claim 31, wherein said at least one
active pharmaceutical ingredient comprises chemical or biological
molecules providing a therapeutic, diagnostic, or prophylactic effect in
vivo.

43. The drug delivery composition of claim 31, wherein said spheroids
comprise said at least one coating from about 0.5 wt % to about 50 wt %
based on the total weight of the spheroid and coating.

44. The drug delivery composition of claim 43, wherein said at least one
coating is from about 1 wt % to about 20 wt %, from about 1 wt % to about
10 wt %, from about 1 wt % to about 7 wt %, from about 3.5 wt % to about
7 wt %, from about 3.5 wt % to about 6 wt %, or from about 4 wt % to
about 5 wt %.

45. The drug delivery composition of claim 43, wherein said at least one
coating is applied to the spheroids to yield a surface area of about 0.1
mg/cm2 to about 20 mg/cm.sup.2.

46. The drug delivery composition of claim 31, wherein the drug delivery
composition is encapsulated or compressed into a tablet and/or caplet.

47. The drug delivery composition of claim 31, wherein the spheroids are
in a capsule and/or sachet.

48. The drug delivery composition of claim 31,whereinthere are different
populations of spheroids.

51. A method for administering the drug delivery composition of claim 1 or
31 to a mammal to provide a timed, pulsed, chronotherapeutic, extended or
controlled release of said at least one active pharmaceutical ingredient.

52. The method of claim 51 for treating a disease for which said at least
one active pharmaceutical ingredient in the drug delivery composition is
effective.

53-56. (canceled)

57. A method for making the drug delivery composition of claim 1, the
method comprising:combining dry materials of the composition to provide a
homogeneous blend;combining the granules with said at least one glidant,
at least one lubricant, and/or at least one oil to provide a wetted mass
suitable for extrusion-spheronization; andextruding the wetted mass to
form the spheroids.

58. The method of claim 57, wherein the wetted mass has a plasticity.

59. The method of claim 57, wherein the wetted mass comprises from about
1:0.7 to about 1:2 of the extrusion aid to said at least one glidant, at
least one lubricant, and/or at least one oil.

60. The method of claim 57, wherein the granules are further combined with
at least one plasticizer.

61. The method of claim 57, wherein after extruding the wetted mass, the
extrudates are charged onto a spheronizer rotating plate and spun to
provide the spheroids.

62. The method of claim 57, wherein the spheroids are dried to provide
spheroids having a water content of less than about 10 wt %.

63. The method of claim 57 further comprising coating the spheroids.

64-66. (canceled)

Description:

FIELD OF THE INVENTION

[0001]The present invention relates to a drug delivery composition. The
present invention also relates to its use and method for making the same.

BACKGROUND OF THE INVENTION

[0002]Many techniques have been used to provide controlled and
sustained-release pharmaceutical dosage forms in order to maintain
therapeutic serum levels of medicaments and to minimize the effects of
missed doses of drugs caused by a lack of patient compliance and the
requirement of decreasing side effects of drugs by controlling their
blood concentration.

[0003]For example, there are extended release tablets which have an
osmotically active drug core surrounded by a semipermeable membrane. The
semipermeable membrane acts to delimit a reservoir chamber. These tablets
function by allowing a fluid, such as gastric or intestinal fluid, to
permeate the coating membrane and dissolve the active ingredient so it
can be released through a passageway in the coating membrane by osmotic
tension or if the active ingredient is insoluble in the permeating fluid,
pushed through the passageway by an expanding agent such as a hydrogel.
Some representative examples of these osmotic tablet devices can be found
in U.S. Pat. Nos. 3,845,770, 3,916,899, 4,034,758, 4,077,407 and
4,783,337. The problem with these devices is that they are tedious and
difficult to fabricate. Their efficiency and precision is also in doubt
as they have been known to break up prematurely or retain some of the
drug content during transit in the gastrointestinal tract, which may lead
to less drug being released and delivered by such devices. It is,
therefore, not uncommon for such devices to contain an overage of drug of
at least 10% to account for such inefficiencies in dose delivery. This
practice is not economical and presents a danger, especially if potent
drugs are used, as these devices have been known to rupture in transit
thus releasing excess dose.

[0004]The development of efficacious pharmaceutical compositions for
controlled or extended release of active pharmaceutical ingredients is
hampered considerably by the fact that current best practices depend
mostly on polymeric matrix tablet systems; for example, sustained-release
devices, such as tablets coated with a release-controlling coat, matrix
tablets comprising water soluble polymeric compounds, matrix tablets
comprising wax, matrix tablets comprising water insoluble polymeric
compounds and the like. For example, U.S. Pat. No. 3,629,393 (Nakamoto)
utilizes a three-component system to provide slow release tablets in
which granules of an active ingredient with a hydrophobic salt of a fatty
acid and a polymer are combined with granules of a hydrocolloid and a
carrier and granules of a carrier and an active or a buffering agent,
which are then directly compressed into tablets. U.S. Pat. No. 3,728,445
(Bardani) discloses slow release tablets formed by mixing an active
ingredient with a solid sugar excipient, granulating the same by
moistening with a cellulose acetate phthalate solution, evaporating the
solvent, recovering the granules and compressing under high pressure.
U.S. Pat. No. 6,645,528 teaches porous drug matrices and methods of
manufacture thereof. Such systems are at a disadvantage because they
allow drug delivery via a singular unit. This presents a high risk
approach to drug delivery as the single unit may be incapacitated during
transit in the gastrointestinal tract or its integrity compromised
leading to dose dumping. Furthermore, the singular unit tablet may be
excreted intact without drug release.

[0005]Therefore, there is a need for drug delivery systems that tend to
have more reproducible upper gastrointestinal transit patterns than the
singular polymeric matrix tablets.

SUMMARY OF THE INVENTION

[0006]In an aspect, there is provided a drug delivery composition
comprising extruded spheroids, the spheroids comprising: at least one
active pharmaceutical ingredient; at least one extrusion-spheronization
aid; at least one superdisintegrant; and at least one glidant, at least
one lubricant, and/or at least one oil.

[0007]In another aspect, there is provided a drug delivery composition
comprising coated spheroids having inert spheroids and at least one
coating for the spheroids, the coating comprising at least one active
pharmaceutical ingredient and at least one superdisintegrant.

[0008]In a further aspect, there is provided a method for administering
the drug delivery composition to a mammal to provide a timed, pulsed,
chronotherapeutic, extended or controlled release of said at least one
active pharmaceutical ingredient.

[0009]In yet a further aspect, there is provided a use of the drug
delivery composition in a medicament for providing a mammal with a timed,
pulsed, chronotherapeutic, extended or controlled release of said at
least one active pharmaceutical ingredient.

[0010]In another aspect, there is provided a use of the drug delivery
composition for providing a mammal with a timed, pulsed,
chronotherapeutic, extended or controlled release of said at least one
active pharmaceutical ingredient.

[0011]In yet another aspect, there is provided a method for making the
drug delivery composition, the method comprising:

[0012]combining dry materials of the composition to provide a homogeneous
blend;

[0013]combining the granules with said at least one glidant, at least one
lubricant, and/or at least one oil to provide a wetted mass suitable for
extrusion-spheronization; and

[0014]extruding the wetted mass to form the spheroids.

[0015]In a further aspect, the wetted mass has a plasticity. In yet a
further aspect, the wetted mass comprises from about 1:0.7 to about 1:2
of the extrusion aid to said at least one glidant, at least one
lubricant, and/or at least one oil.

[0016]The novel features of the present invention will become apparent to
those of skill in the art upon examination of the following detailed
description of the invention. It should be understood, however, that the
detailed description of the invention and the specific examples
presented, while indicating certain embodiments of the present invention,
are provided for illustration purposes only because various changes and
modifications within the spirit and scope of the invention will become
apparent to those of skill in the art from the detailed description of
the invention and claims that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017]Certain embodiments of the present invention will now be described
more fully with reference to the accompanying drawings:

[0018]FIG. 1 is a dissolution profile for capsules of Example 3; and

[0019]FIG. 2 is a dissolution profile for tablets of Example 3.

DETAILED DESCRIPTION OF THE INVENTION

[0020]The present invention is directed to a drug delivery composition and
to a method of using and preparing same in order to control the rate and
extent of delivery of active pharmaceutical ingredient(s) in mammals.

[0021]In one embodiment, the drug delivery composition comprises
spheroids. The spheroids comprise at least one active pharmaceutical
ingredient; at least one extrusion-spheronization aid; at least one
superdisintegrant; and at least one glidant, at least one lubricant,
and/or at least one oil.

[0022]The spheroids can further comprise at least one carbomer, at least
one buffering agent, at least one electrolyte, zein, and/or water. The
spheroids of the composition can be made by extrusion, typically, an
extrusion-spheronization process.

[0023]The spheroids can comprise from about 0.1 wt % to about 80 wt % of
at least one active pharmaceutical ingredient, from about 10 wt % to
about 90 wt % of at least one extrusion-spheronization aid, from about
0.1 wt % to about 70 wt % of at least one superdisintegrant, from about
0.1 wt % to about 70 wt % of at least one glidant, from about 0.1 wt % to
about 70 wt % of at least one lubricant, and from about 0.1 wt % to about
50 wt % of at least one oil. Optionally, the spheroids can further
comprise from about 0 wt % to about 50 wt % of at least one carbomer,
from about 0 wt % to about 25 wt % of at least one buffering agent, from
about 0 wt % to about 55 wt % of at least one electrolyte, from about 0
wt % to about 25 wt % of zein, and/or from about 0 wt % to about 10 wt %
of water. These wt % are based on the total weight of the spheroid.

[0024]Further embodiments of the spheroids include:

[0025]The active pharmaceutical ingredient can also be present of from
about 5 wt % to about 70 wt %; about 10 wt % to about 70 wt %; about 20
wt % to about 60 wt %; about 30 wt % to about 60 wt %; or from about 40
wt % to about 60 wt %.

[0026]The extrusion-spheronization aid can also be present of from about
10 wt % to about 70 wt %; from about 20 wt % to about 70 wt %; about 30
wt % to about 70 wt %; about 40 wt % to about 70 wt %; about 50 wt % to
about 70 wt %; or from about 55 wt % to about 70 wt %.

[0027]The superdisintegrant can also be present of from about 2 wt % to
about 70 wt %; from about 20 wt % to about 70 wt %; about 30 wt % to
about 70 wt %; about 40 wt % to about 70 wt %; about 50 wt % to about 70
wt %; or from about 55 wt % to about 70 wt %.

[0028]The glidant can also be present of from about 1 wt % to about 20 wt
%; from about 1 wt % to about 15 wt %; from about 2 wt % to about 15 wt
%; from about 5 wt % to about 15 wt %; or from about 5 wt % to. about 10
wt %.

[0029]The lubricant can also be present of from about 0.5 wt % to about 5
wt %; from about 0.5 wt % to about 4 wt %; from about 0.5 wt % to about 3
wt %; from about 0.5 wt % to about 2 wt %; or from about 1 wt % to about
2 wt %.

[0030]The oil can also be present of from about 0.5 wt % to about 5 wt %;
from about 0.5 wt % to about 4 wt %; from about 0.5 wt % to about 3 wt %;
from about 0.5 wt % to about 2 wt %; or from about 1 wt % to about 2 wt
%.

[0031]Spheroids of drug delivery compositions tend to have more
reproducible upper GI transit patterns than the singular polymeric matrix
tablets, for example, if dosing in the fed and fasted states is compared.
Since GI transit time is an important parameter relevant to the
variability of plasma concentration during drug delivery, this makes the
use of multi-particulate drug delivery compositions, such as spheroids,
more desirable than singular polymeric matrix systems. The use of a
multi-particulate drug delivery composition instead of a singular
polymeric matrix tablet is more advantageous since the multi-particulate
drug delivery composition can contain a plurality of spheroids containing
drugs. Therefore, the loss of integrity of a few spheroids is not going
to be statistically significant as compared to the singular polymeric
matrix tablet of the prior art. Therefore, the delivery of many
therapeutic agents will be most effective when made available as a
multi-particulate drug delivery composition.

[0032]The spheroids of the drug delivery composition described above can
also be coated, for example, with at least one layer of a polymeric film
coat; at least one layer of enteric coat; at least one layer of
non-enteric coat; and/or at least one layer of semi-permeable membrane
coat. Typically, the coating is from about 0.5 wt % to about 50 wt %
based on the total weight of the spheroid and coating. More typically,
the coating is from about 1 wt % to about 20 wt %, from about 1 wt % to
about 10 wt %, from about 1 wt % to about 7 wt %, from about 3.5 wt % to
about 7 wt %, from about 3.5 wt % to about 6 wt %, or from about 4 wt %
to about 5 wt %. Also, there may be more than one layer of coatings, for
example, two to three layers of coatings.

[0033]The weight percentages of the components in the coating described
herein are based on the weight of the coating.

[0034]Any suitable coating may be used for the spheroids of the invention.
For example, the coatings can include:

[0035]An enteric coating which can comprise at least one enteric material
and at least one superdisintegrant. Optionally, the coating further
comprises at least one wicking agent, carragenaan, and at least one
plasticizer. Typically, the coating comprises from about 10 wt % to about
90 wt % of the enteric material, such as cellulose esters or
polymethacrylates; from about 0.5 wt % to about 60 wt % of the
superdisintegrant; from about 0 wt % to about 60 wt % of the wicking
agent, such as microcrystalline cellulose; from about 0 wt % to about 60
wt % carragenaan and from about 0 wt % to about 25 wt % of the
plasticizer, such as polyethylene glycol.

[0036]A non-enteric coating which can comprise at least one non-enteric
material and at least one superdisintegrant. Optionally, the coating
further comprises at least one wicking agent, carragenaan, and at least
one plasticizer. Typically, the coating comprises from about 10 wt % to
about 90 wt % of the non-enteric material, such as ethylcellulose and/or
polyvinylacetate; from about 0.5 wt % to about 60 wt % of the
superdisintegrant; from about 0 wt % to about 60 wt % of the wicking
agent, such as microcrystalline cellulose; from about 0 wt % to about 60
wt % carragenaan and from about 0 wt % to about 25 wt % of the
plasticizer, such as polyethylene glycol.

[0037]A semi-permeable membrane coating which can comprise at least one
semi-permeable membrane material and at least one superdisintegrant.
Optionally, the coating further comprises at least one wicking agent,
carragenaan, and at least one plasticizer. Typically, the coating
comprises from about 10 wt % to about 90 wt % of the semi-permeable
membrane material, such as cellulose acetate phthalate; from about 0.5 wt
% to about 60 wt % of the superdisintegrant; from about 0 wt % to about
60 wt % of the wicking agent, such as microcrystalline cellulose; from
about 0 wt % to about 60 wt % carragenaan and from about 0 wt % to about
25 wt % of the plasticizer, such as polyethylene glycol.

[0038]Further embodiments of the coating composition include:

[0039]The enteric material can also be present in the coating of from
about 5 wt % to about 90 wt %; from about 10 wt % to about 80 wt %; from
about 20 wt % to about 80 wt %; from about 30 wt % to about 70 wt %; or
from about 40 wt % to about 70 wt %.

[0040]The non-enteric material can also be present in the coating of from
about 5 wt % to about 90 wt %; from about 10 wt % to about 80 wt %; from
about 20 wt % to about 80 wt %; from about 30 wt % to about 70 wt %; or
from about 40 wt % to about 70 wt %.

[0041]The semi-permeable membrane material can also be present in the
coating of from about 5 wt % to about 90 wt %; from about 10 wt % to
about 80 wt %; from about 20 wt % to about 80 wt %; from about 30 wt % to
about 70 wt %; or from about 40 wt % to about 70 wt %.

[0042]The superdisintegrant can also be present in the coating of from
about 0.5 wt % to about 55 wt %; from about 0.5 wt % to about 40 wt %;
from about 0.5 wt % to about 30 wt %; from about 1 wt % to about 20 wt %;
or from about 10 wt % to about 20 wt %.

[0043]The wicking agent can also be present in the coating of from about
0.5 wt % to about 55 wt %; from about 0.5 wt % to about 50 wt %; from
about 0.5 wt % to about 40 wt %; from about 5 wt % to about 40 wt %; or
from about 20 wt % to about 40 wt %.

[0044]Carragenaan can also be present in the coating of from about 0.5 wt
% to about 55 wt %; from about 0.5 wt % to about 50 wt %; from about 0.5
wt % to about 40 wt %; from about 5 wt % to about 40 wt %; or from about
20 wt % to about 40 wt %.

[0045]The plasticizer can also be present in the coating of from about 0.5
wt % to about 25 wt %; from about 1 wt % to about 20 wt %; from about 5
wt % to about 20 wt %; from about 5 wt % to about 15 wt %; or from about
1 wt % to about 5 wt %.

[0046]In a specific embodiment, the coating of the coated spheroids
comprises from about 10 wt % to about 90 wt % of the enteric material,
such as cellulose esters and/or polymethacrylates; from about 0.5 wt % to
about 60 wt % of the superdisintegrant; from about 0.5 wt % to about 60
wt % of the wicking agent, such as microcrystalline cellulose; from about
0 wt % to about 60 wt % carragenaan and from about 0 wt % to about 25 wt
% plasticizer, such as polyethylene glycol.

[0047]In a further embodiment, the coating of the coated spheroids
comprises from about 10 wt % to about 90 wt % of the non-enteric
material, such as ethylcellulose and/or polyvinylacetate; from about 0.5
wt % to about 60 wt % of the superdisintegrant; from about 0.5 wt % to
about 60 wt % of the wicking agent, such as microcrystalline cellulose;
from about 0 wt % to about 60 wt % carragenaan and from about 0 wt % to
about 25 wt % plasticizer, such as polyethylene glycol. In still a
further embodiment, the coating of the coated spheroids comprises from
about 10 wt % to about 90 wt % of the semi-permeable membrane material
such as cellulose acetate phthalate; from about 0.5 wt % to about 60 wt %
of a superdisintegrant; from about 0.5 wt % to about 60 wt % of a wicking
agent, such as microcrystalline cellulose; from about 0 wt % to about 60
wt % carragenaan and from about 0 wt % to about 25 wt % plasticizer, such
as polyethylene glycol.

[0048]In another embodiment, the coating of the coated spheroids comprises
from about 10 wt % to about 90 wt % polyvinylacetate and/or
ethylcellulose; from about 0.5 wt % to about 60 wt % of a
superdisintegrant; from about 0.5 wt % to about 60 wt % of a wicking
agent, such as microcrystalline cellulose; from about 0 wt % to about 60
wt % carragenaan and from about 0 wt % to about 25 wt % plasticizer, such
as polyethylene glycol.

[0049]The spheroids (e.g. with or without coating) of the composition may
be encapsulated (e.g. placed within a capsule) and/or compressed into,
for example, tablet(s) and/or caplet(s) and/or combined within a sachet.
For example, at least one population of spheroids coated with at least
one layer of a polymeric film coat are encapsulated or compressed into at
least one tablet. In yet another example, at least one population of
spheroids coated with at least one layer of enteric coat are encapsulated
or compressed into at least one tablet. In a further example, at least
one population of spheroids coated with at least one layer of non-enteric
coat are encapsulated or compressed into at least one tablet. In still a
further example, at least one population of spheroids coated with at
least one layer of semi-permeable membrane coat are encapsulated or
compressed into at least one tablet.

[0050]The drug delivery composition can also comprise coated inert
spheroids. Any suitable coating of the inert spheroids is a coating
composition that comprises at least one active pharmaceutical ingredient.

[0051]In embodiments, the coating can include at least one active
pharmaceutical ingredient and at least one superdisintegrant. Typically,
the coating comprises from about 0.1 wt % to about 80 wt % of at least
one active pharmaceutical ingredient and from about 0.5 wt % to about 60
wt % of the superdisintegrant. Optionally, the coating can further
comprise at least one wicking agent, carragenaan, at least one
plasticizer, at least one electrolyte, at least one oil, at least one
water soluble gellable polymer, at least one water insoluble
organosoluble polymer, at least one glidant, at least one buffering
agent, and water. Typically, from about 0 wt % to about 60 wt % of a
wicking agent; from about 0 wt % to about 60 wt % carragenaan; from about
0 wt % to about 25 wt % plasticizer, such as polyethylene glycol; from
about 0 wt % to about 55 wt % of at least one electrolyte, from about 0
wt % to about 55 wt % of at least one oil, from about 0 wt % to about 50
wt % at least one water soluble gellable polymer, from about 0 wt % to
about 50 wt % at least one water insoluble organosoluble polymer, from
about 0 wt % to about 25 wt % of at least one glidant, from about 0 wt %
to about 25 wt % of at least one buffering agent, and/or from about 0 wt
% to about 10 wt % of water.

[0052]Further embodiments of the coating composition for the inert
spheroids include:

[0053]The active pharmaceutical ingredient can also be present in the
coating of from about 0.5 wt % to about 90 wt %; from about 10 wt % to
about 80 wt %; from about 20 wt % to about 80 wt %; from about 30 wt % to
about 70 wt %; or from about 40 wt % to about 70 wt %.

[0054]The superdisintegrant can also be present in the coating of from
about 0.5 wt % to about 55 wt %; from about 0.5 wt % to about 40 wt %;
from about 0.5 wt % to about 30 wt %; from about 1 wt % to about 20 wt %;
or from about 10 wt % to about 20 wt %.

[0055]The wicking agent can also be present in the coating of from about
0.5 wt % to about 90 wt %; from about 0.5 wt % to about 80 wt %; from
about 0.5 wt % to about 70 wt %; from about 5 wt % to about 60 wt %; or
from about 20 wt % to about 60 wt %.

[0056]Carragenaan can also be present in the coating of from about 0.5 wt
% to about 90 wt %; from about 0.5 wt % to about 80 wt %; from about 0.5
wt % to about 70 wt %; from about 5 wt % to about 60 wt %; or from about
20 wt % to about 60 wt %.

[0057]The plasticizer can also be present in the coating of from about 0.5
wt % to about 25 wt %; from about 1 wt % to about 20 wt %; from about 5
wt % to about 20 wt %; from about 5 wt % to about 15 wt %; or from about
1 wt % to about 5 wt %.

[0058]In a specific embodiment, the coating composition comprises from
about 0.1 wt % to about 80 wt % of at least one active pharmaceutical
ingredient; from about 0.5 wt % to about 60 wt % of a superdisintegrant;
from about 0.5 wt % to about 60 wt % of a wicking agent, such as
microcrystalline cellulose and/or pectin; from about 0 wt % to about 60
wt % carragenaan and from about 0 wt % to about 25 wt % plasticizer, such
as polyethylene glycol. The coating composition can further comprise from
about 0 wt % to about 55 wt % of at least one electrolyte, from about 0
wt % to about 55 wt % of at least one oil, from about 0 wt % to about 90
wt % of at least one plasticizer, from about 0 wt % to about 50 wt % at
least one water soluble gellable polymer, from about 0 wt % to about 50
wt % at least one water insoluble organosoluble polymer, from about 0 wt
% to about 25 wt % of at least one glidant, from about 0 wt % to about 25
wt % of at least one buffering agent, and/or from about 0 wt % to about
10 wt % of water.

[0059]In certain embodiments, there is from about 10 wt % to about 90 wt %
of the inert spheroids and from about 0.5 wt % to about 50 wt % of the
coating composition. The coating composition comprises from about 0.1 wt
% to about 80 wt % of at least one active pharmaceutical ingredient, from
about 0.1 wt % to about 50 wt % of at least one superdisintegrant, from
about 0.5 wt % to about 90 wt % of a wicking agent, and from about 0.5 wt
% to about 90 wt % of carrageenan. Typically, the coating composition
comprises from about 0.1 wt % to about 80 wt % of at least one active
pharmaceutical ingredient, about 0.1 wt % to about 50 wt % of at least
one superdisintegrant, from about 0.5 wt % to about 90 wt % of
microcrystalline cellulose, and from about 0.5 wt % to about 90 wt % of
carrageenan. Optionally, the coating composition can further comprise
from about 0 wt % to about 55 wt % of at least one electrolyte, from
about 0 wt % to about 55 wt % of at least one oil, from about 0 wt % to
about 90 wt % polyethylene glycol, from about 0 wt % to about 50 wt %
hydroxypropylmethyl cellulose, from about 0 wt % to about 50 wt %
polyvinyl acetate, from about 0 wt % to about 25 wt % of at least one
glidant, from about 0 wt % to about 25 wt % of at least one buffering
agent, and/or from about 0 wt % to about 10 wt % of water.

[0060]Examples of inert spheroids that may be used are any
pharmaceutically acceptable, inert spheroid such as, and without being
limited thereto, sugar spheroids, starch spheroids and/or cellulose
spheroids.

[0061]The spheroids and/or coated spheroids of the present invention can
be any suitable size for drug delivery. The spheroids may have a diameter
of less than about 6 mm; from about 0.01 mm to about 5.0 mm; or from
about 0.15 mm to about 5 mm.

[0062]The coating is typically applied to the spheroid to yield a surface
area of about 0.1 mg/cm2 to about 20 mg/cm2.

[0063]The drug delivery composition embodiments of the present invention
can be used for providing a mammal with a timed, pulsed,
chronotherapeutic, extended or controlled release of at least one active
pharmaceutical ingredient. The drug delivery composition of the present
invention may be in any suitable form that provides release of the
spheroids. For example, the composition can be in the form of a tablet or
capsule such as, encapsulating (e.g. placed within a capsule) or
compressing into a tablet at least one population of spheroids. The
tablets or capsules themselves can also be coated, for example, with a
polymeric film, such as polymethacrylate copolymers, to provide a timed,
pulsed, chronotherapeutic, extended or controlled release of at least one
active pharmaceutical ingredient.

[0064]In an embodiment, there is provided a method for treating a disease
for which at least one active pharmaceutical ingredient in the drug
delivery composition is effective. The method comprises administering to
a mammal in need of such treatment the timed, pulsed, chronotherapeutic,
controlled or extended release drug delivery composition of the present
invention.

[0066]The drug delivery composition can dissolve rapidly, instantaneously
or melt in the mouth, releasing the spheroids. In a specific embodiment,
the drug delivery composition has a dissolution profile wherein from
about 0% to 50% of active pharmaceutical ingredient(s) is released in the
first hour and greater than about 70% is released in approximately 24
hours.

[0067]For various rates of release, various populations of spheroids may
be used. For example, to obtain pulsed release, a coated population of
spheroids can be combined with an uncoated population of spheroids and
encapsulated in a capsule or compressed into a tablet. Alternatively,
coated spheroids with different release rates can be combined together
and encapsulated in a capsule or compressed into a tablet.

Method of Making Drug Delivery Composition

[0068]The spheroids can be prepared by extrusion-spheronization. In
addition, drug-powder or drug solution layering can be used to coat the
spheroids. In such an embodiment, the spheroids themselves can be inert
and the coating itself contain the active pharmaceutical ingredient(s).

[0069]When preparing the spheroids, including coated spheroids, liquids
tend to migrate to the surface of spheroids and induce surface
plasticity. At very low levels, the surface moisture contributes to
lubrication and enhances spheroid movement. At high levels, and
especially at reduced ratios of the extrusion-spheronization aid, the
liquid may cause the spheroids to stick to one another and the
spheronizer wall. It may also lead to uncontrolled granule growth and
wide distribution of particle size and, therefore, the batch may be
destroyed. This underscores the relationship that exists between the
amount of liquid for lubrication and the production of spheroids that are
free from agglomeration. The drug delivery composition of the present
invention introduces a high margin of formulation tolerance which brings
about a balance between rigidity and plasticity of the spheroids. Using
the method described herein, spheroids within a narrow size distribution
range can be manufactured conveniently and consistently. This method
lowers the chance of material being discarded or reworked after a
production run due to a low yield in the required size range.

[0070]Good extrudates and spheroids can be obtained from the spheroid
compositions described herein, for example, a composition comprising from
about 0.1 wt % to about 80 wt % of at least one active pharmaceutical
ingredient, from about 10 wt % to about 90 wt % of at least one
extrusion-spheronization aid, from about 0.1 wt % to about 70 wt % of at
least one superdisintegrant, from about 0.1 wt % to about 70 wt % of at
least one glidant, from about 0.1 wt % to about 70 wt % of at least one
lubricant, and from about 0.1 wt % to about 50 wt % of at least one oil.
Optionally, the spheroids can further comprise from about 0 wt % to about
50 wt % of at least one carbomer, from about 0 wt % to about 25 wt % of
at least one buffering agent, from about 0 wt % to about 55 wt % of at
least one electrolyte, from about 0 wt % to about 25 wt % of zein, and/or
from about 0 wt % to about 10 wt % of water.

[0071]In an embodiment, to produce spheroids using
extrusion-spheronization, extrudates are prepared by first blending the
dry materials of the composition in a planetary mixer for a suitable time
to provide a homogeneous blend; typically, for about 5 minutes. The
homogeneous blend is granulated for about 5 minutes using at least one
glidant, at least one lubricant, and/or at least one oil such as, for
example, water, oil and, sometimes, an aqueous solution of plasticizer.
The granulation time, end point and amount of granulation liquid is
determined by the behavior (e.g. should have a plasticity) of a resultant
wetted mass during extrusion-spheronization operation. Typically, from
about 1:0.7 to about 1:2 of the extrusion aid to the at least one
glidant, at least one lubricant, and/or at least one oil is used to form
the resultant wetted mass. For example, from about 100 wt %:70 wt % to
about 100 wt %:200 wt % of the extrusion aid to the at least one glidant,
at least one lubricant, and/or at least one oil is used to form the
resultant wetted mass. The wetted mass is passed through the extruder to
form rods. The extrudates are charged onto the spheronizer rotating plate
and spun at a predetermined rpm for about 30 seconds to about 5 minutes
or for a suitable time to provide spheroids. The spheroids are harvested
and dried. In an embodiment, the spheroids are dried to provide spheroids
having a water content of less than about 10 wt %. In a specific
embodiment, the spheroids are dried at about 40° C. for about 16
hours in a tray drier oven to provide a water content of less than about
10 wt %. The granulation solution serves as binder, and together with
lubricants, oils and glidants listed above aid the
extrusion-spheronization process.

[0072]To coat spheroids, a coating composition such as, and without being
limited thereto, a solution, a dispersion or a suspension of the coating
composition, is coated onto the spheroids. The spheroids can have no
coating or already have at least one coating prior to the coating with
the coating composition. The coating composition can be applied using any
suitable coating process used in the pharmaceutical industry that
substantially maintains the integrity of a majority of the spheroids. For
example, a fluid bed, powder layering and/or a centrifugal process may be
used. The coating method can be repeated to provide more than one coating
layer.

[0073]The coating composition can comprise a polymeric film, an enteric
material; a non-enteric material; and/or a semi-permeable membrane
material. Typically, the resultant coating is from about 0.5 wt % to
about 50 wt % based on the total weight of the spheroid and coating.

[0074]In a specific embodiment, the coating composition comprises from
about 10 wt % to about 90 wt % of the enteric material, such as cellulose
esters and/or polymethacrylates; from about 0.5 wt % to about 60 wt % of
the superdisintegrant; from about 0.5 wt % to about 60 wt % of the
wicking agent, such as microcrystalline cellulose; from about 0 wt % to
about 60 wt % carragenaan and from about 0 wt % to about 25 wt %
plasticizer, such as polyethylene glycol.

[0075]In a further embodiment, the coating composition comprises from
about 10 wt % to about 90 wt % of the non-enteric material, such as
ethylcellulose and/or polyvinylacetate; from about 0.5 wt % to about 60
wt % of the superdisintegrant; from about 0.5 wt % to about 60 wt % of
the wicking agent, such as microcrystalline cellulose; from about 0 wt %
to about 60 wt % carragenaan and from about 0 wt % to about 25 wt %
plasticizer, such as polyethylene glycol. In still a further embodiment,
the coating composition comprises from about 10 wt % to about 90 wt % of
the semi-permeable membrane material such as cellulose acetate phthalate;
from about 0.5 wt % to about 60 wt % of a superdisintegrant; from about
0.5 wt % to about 60 wt % of a wicking agent, such as microcrystalline
cellulose; from about 0 wt % to about 60 wt % carragenaan and from about
0 wt % to about 25 wt % plasticizer, such as polyethylene glycol.

[0076]In another embodiment, the coating composition comprises from about
10 wt % to about 90 wt % polyvinylacetate and/or ethylcellulose; from
about 0.5 wt % to about 60 wt % of a superdisintegrant; from about 0.5 wt
% to about 60 wt % of a wicking agent, such as microcrystalline
cellulose; from about 0 wt % to about 60 wt % carragenaan and from about
0 wt % to about 25 wt % plasticizer, such as polyethylene glycol.

[0077]To coat an inert spheroid, a similar method as described above can
be used. The coating composition comprises from about 0.1 wt % to about
80 wt % of at least one active pharmaceutical ingredient and from about
0.5 wt % to about 60 wt % of the superdisintegrant. Optionally, the
coating can further comprise at least one wicking agent, carragenaan, at
least one plasticizer, at least one electrolyte, at least one oil, at
least one water soluble gellable polymer, at least one water insoluble
organosoluble polymer, at least one glidant, at least one buffering
agent, and water. For example, a solution, a dispersion or a suspension
of the coating composition is coated onto the inert spheroids. The
spheroids can have no coating or already have at least one coating prior
to coating with the coating composition. The coating composition can be
applied using any suitable coating process used in the pharmaceutical
industry that substantially maintains the integrity of a majority of the
spheroids. For example, a fluid bed, powder layering and/or a centrifugal
process may be used. The inert spheroids can be, for example, sugar,
starch and/or cellulose spheroids.

[0078]In another embodiment, the coating composition can be applied using
powder layering in a coating pan. The coating composition is added to the
inert spheroids while rotating the coating pan. The solution is
evaporated leaving behind layers of active pharmaceutical ingredient(s)
surrounding the spheroids.

[0079]Once the coated spheroids are formed as described herein, the
spheroids can be further coated. The coated spheroids can also be further
coated with one or more layers of a polymeric film.

[0081]A description of these and other classes of useful drugs and a
listing of species within each class can be found in Martindale, The
Extra Pharmacopoeia, 30th Ed. (The Pharmaceutical Press, London 1993).

[0084]With respect to extrusion-spheronization aids, any suitable
extrusion-spheronization aids such as microcrystalline cellulose, pectin
and ethylcellulose.

[0085]With respect to superdisintegrants, any superdisintegrants that can
improve and modulate the release of the active pharmaceutical
ingredient(s) are suitable. For example and without being limited
thereto, sodium starch glycolate, sodium croscarmellose, homopolymer of
cross-linked N-vinyl-2-pyrrolidone, and alginic acid, a cross-linked
cellulose, a cross-linked polymer, a cross-linked starch, ion-exchange
resin, crospovidone and combinations thereof.

[0090]With respect to electrolytes, any suitable electrolyte can be used
such as one or more salts capable of providing, sodium (Na.sup.+),
potassium (K.sup.+), chloride (Cl.sup.-), calcium (Ca2+), magnesium
(Mg2+), bicarbonate (HCO3.sup.-); phosphate (PO42-),
and sulfate (SO42-) ions.

[0091]Examples of polymeric films include polymethacrylates copolymer and
enteric materials.

[0096]The term "timed release", "pulsed release", "chronotherapeutic
release", "extended release" and "controlled release" are defined for
purposes of the present invention as the release of the drug from the
dosage form at such a rate that when a dose of the drug is administered
in the timed release, pulsed release, chronotherapeutic release, extended
release or controlled-release form, blood (e.g., plasma) concentrations
(levels) of the drug are maintained within the therapeutic range but
below toxic levels over a selected period of time.

[0097]When introducing elements disclosed herein, the articles "a", "an",
"the", and "said" are intended to mean that there are one or more of the
elements unless the context dictates otherwise. For example, the term "a
compound" and "at least one compound" may include a plurality of
compounds, including mixtures thereof. The terms "comprising", "having",
"including" are intended to be open-ended and mean that there may be
additional elements other than the listed elements.

[0098]The above disclosure generally describes the present invention. A
more complete understanding can be obtained by reference to the following
specific Examples. The Examples are described solely for purposes of
illustration and are not intended to limit the scope of the invention.
Changes in form and substitution of equivalents are contemplated as
circumstances may suggest or render expedient. Although specific terms
have been employed herein, such terms are intended in a descriptive sense
and not for purposes of limitation.

EXAMPLES

Example 1

Controlled Release Methylphenidate HCl Spheroids

[0099]This was a two step process in which immediate release spheroids
were manufactured by an extrusion-spheronization process followed by
application of a controlled release coating on the spheroids to form
controlled release spheroids.

With respect to each formulation, the materials were charged into a
planetary mixer and blended for about 5 minutes. The resultant
homogeneous blend was granulated for about 3 minutes with the sufficient
quantity of water with respect to Formulation I and Formulation II, while
an aqueous suspension of ethylcellulose (commercial brand Aquacoat®)
was used for Formulation III. The wet mass was extruded using a Caleva
extruder Model 25. The extrudates were spheronised in about 500 gram
quantities in a Caleva spheroniser Model 240. The wet spheroids were
dried at about 40° C. in a tray dryer oven to LOD (loss on drying)
of less than about 2 wt %.

(2) Coating of Spheroid

[0100]About 1000 g of the spheroids from Formulation I were coated with an
aqueous dispersion composed of about 500 g of Aquacoat® (e.g.
ethylcellulose dispersion), about 40 g LustreClear® (e.g. carrageenan
and microcrystalline cellulose), about 35.5 g of dibutyl sabate, and
about 114 g of water. The spheroids were coated to a weight gain of about
6% of the spheroid weight.

[0101]About 1000 g of the spheroids from Formulation II were coated with
an aqueous dispersion composed of about 500 g of Aquacoat® (e.g.
ethylcellulose dispersion), about 40 g LustreClear® (e.g. carrageenan
and microcrystalline cellulose), about 36 g of dibutyl sabate, and about
114 g of water. The spheroids were coated to a weight gain of about 6% of
the spheroid weight.

[0102]About 1250 g of the spheroids from Formulation III were coated with
an aqueous dispersion composed of about 350 g of Aquacoat® (e.g.
ethylcellulose dispersion), about 36 g of dibutyl sabate, 20 g of pigment
and about 72 g of water. The spheroids were coated to a weight gain of
about 12% of the spheroid weight.

[0103]Coating was done in a UniGlatt fluid bed coater using a top spray
assembly. The coated spheroids were dried in a tray dryer oven for about
2 hours at about 60° C.

Example 2

Pulsed Release Venlafaxine HCl Capsules or Tablets

[0104]This was a three step process in which immediate release spheroids
were manufactured by an extrusion-spheronization process followed by
application of a controlled release coat on some of the spheroids. To
obtain pulsed release, a coated population of spheroids were combined
with an uncoated population of spheroids and encapsulated in a capsule or
compressed into a tablet. Alternatively, coated spheroids with different
release rates were combined together and encapsulated in a capsule or
compressed into a tablet.

With respect to each formulation, the materials were charged into a
planetary mixer and blended for about 5 minutes. The resultant
homogeneous blend was granulated for about 3 minutes with the sufficient
quantity of water. The wet mass was extruded using a Caleva extruder
Model 25. The extrudates were spheronised in about 500 gram quantities in
a Caleva spheroniser Model 240. The wet spheroids were dried at about
40° C. in a tray dryer oven to LOD (loss on drying) of less than
about 2 wt %.

(2) Coating of Immediate Release Spheroids

[0106]About 1000 g of the spheroids from Formulation IV were coated with
an aqueous dispersion composed of about 500 g of Aquacoat® (e.g.
ethylcellulose dispersion), about 40 g LustreClear® (e.g. carrageenan
and microcrystalline cellulose), about 36 g of dibutyl sabate, and about
114 g of water. The spheroids were coated to a weight gain of about 6% of
the spheroid weight to yield Formulation IVa, while Formulation V was
coated to a weight gain of 15% of the spheroid weight using a similar
aqueous dispersion to yield Formulation Va.

[0107]Coating was done in a UniGlatt fluid bed coater using a top spray
assembly. The coated spheroids were dried in a tray dryer oven for about
2 hours at about 60° C.

[0109]Type 2 is made of a blend of 30 wt % Formulation IV, and 70 wt %
Formulation Va.

Type 3

[0110]Type 3 is made of a blend of 40 wt % Formulation IVa and 60 wt %
Formulation Va.These combinations (Type 1, Type 2 or Type 3) were
encapsulated or compressed into tablets.

Example 3

Chronotherapeutic or Timed Release Carvedilol Capsules or Tablets

[0111]This was a three step process in which immediate release spheroids
were manufactured by a solution layering process in a fluid bed coater
followed by application of a controlled release coat on the spheroids. To
obtain chronotherapeutic release, a controlled release coated population
of spheroids were coated with methacrylic acid copolymer and/or cellulose
esters and encapsulated in a capsule. Alternatively, a controlled release
coated population of spheroids were compressed into a tablet and the
tablet was coated with methacrylic acid copolymer and/or cellulose
esters.

With respect to each formulation, Carvedilol and crospovidone were slowly
added to an aqueous solution of LustreClear® and/or Opadry® and
mixed well. Sugar spheres (18-20 mesh) were coated with the drug
suspension in a UniGlatt fluid bed coater. The spheroids were coated to a
weight gain of about 10% of the spheroid weight. The spheroids were dried
to LOD (loss on drying) of less than about 2 wt %.

(2) Manufacture of Controlled Release Spheroids

[0113]About 1000 g of the spheroids from Formulation VI were coated with
an aqueous dispersion composed of about 500 g of Aquacoat® (e.g.
ethylcellulose dispersion), about 40 g LustreClear® (e.g. carrageenan
and microcrystalline cellulose), about 35.5 g of dibutyl sabate, and
about 114 g of water. The spheroids were coated to a weight gain of about
6% of the spheroid weight.

[0114]About 1000 g of the spheroids from Formulation VII were coated with
an aqueous dispersion composed of about 500 g of Aquacoat® (e.g.
ethylcellulose dispersion), about 40 g LustreClear® (e.g. carrageenan
and microcrystalline cellulose), about 36 g of dibutyl sabate, and about
114 g of water. The spheroids were coated to a weight gain of about 6% of
the spheroid weight.

[0115]About 1000 g of the spheroids from Formulation VIII were coated with
an aqueous dispersion composed of about 500 g of Aquacoat® (e.g.
ethylcellulose dispersion), about 40 g LustreClear® (e.g. carrageenan
and microcrystalline cellulose), about 36 g of dibutyl sabate, and about
114 g of water. The spheroids were coated to a weight gain of about 6% of
the spheroid weight.

[0116]About 1000 g of the spheroids from Formulation VI were coated with
an aqueous dispersion composed of about 400 g of Eudragit NE30D® and
about 60 g of talc to a weight gain of about 6% of the spheroid weight.

[0117]About 1000 g of the spheroids from Formulation VII were coated with
an aqueous dispersion composed of about 400 g of Eudragit NE30D® and
about 60 g of talc to a weight gain of about 6% of the spheroid weight.

[0118]About 1000 g of the spheroids from Formulation VIII were coated with
an aqueous dispersion composed of about 400 g of Eudragit NE30D® and
about

60 g of talc to a weight gain of about 6% of the spheroid weight.

[0119]Coating was done in a UniGlatt fluid bed coater using a top spray
assembly. The coated spheroids were dried in a tray dryer oven for about
2 hours at about 60° C.

(3) Manufacture of Chronotherapeutic or Timed Release Carvedilol

(I) Capsules

[0120]The controlled release spheroids were coated with an aqueous
dispersion composed of about 1142 g of Eudragit L30D55® (e.g.
methacrylic acid copolymer), about 137 g of glycerol monostearate, about
41 g of triacetyl citrate, and about 679 g of water and/or an aqueous
dispersion composed of about 1142 g of cellulose esters, about 137 g of
glycerol monostearate, about 41 g of triacetyl citrate, and about 679 g
of water to a weight gain sufficient to give a lag time of about 1 hour
to about 12 hours as desired. These are then encapsulated in a capsule.
FIG. 1 shows a dissolution profile for these capsules.

(II) Tablets

[0121]The controlled release coated population of spheroids and/or inert
spheroids were compressed into a tablet and the tablet was coated an
aqueous dispersion composed of about 1142 g of Eudragit L30D55TM
(e.g. methacrylic acid copolymer), about 137 g of glycerol monostearate,
about 41 g of triacetyl citrate, and about 679 g of water and/or an
aqueous dispersion composed of about 1142 g of cellulose esters, about
137 g of glycerol monostearate, about 41 g of triacetyl citrate, and
about 679 g of water to a weight gain sufficient to give a lag time of
about 1 hour to about 12 hours as desired. FIG. 2 shows a dissolution
profile for these tablets.